Elsevier

Respiratory Medicine

Volume 109, Issue 1, January 2015, Pages 63-73
Respiratory Medicine

A randomized, three-period crossover study of umeclidinium as monotherapy in adult patients with asthma

https://doi.org/10.1016/j.rmed.2014.10.009Get rights and content
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Summary

Background

To our knowledge, no studies in patients with asthma have assessed a long-acting muscarinic antagonist in the absence of inhaled corticosteroids (ICS).

Objective

Evaluate the dose–response, efficacy, and safety of umeclidinium (UMEC) in patients with asthma not receiving ICS.

Methods

In this double-blind, three-period crossover study, 350 subjects were randomized to a sequence of three of eight inhaled treatments: UMEC 15.6, 31.25, 62.5, 125, or 250 mcg once daily (OD), UMEC 15.6 or 31.25 mcg twice daily (BID), or placebo, administered for 14 days (12–14-day washout). Trough forced expiratory volume in one second (FEV1), 0–24-h weighted mean (WM) FEV1, and safety were assessed. Serial spirometry and pharmacokinetic assessments were performed in a subgroup.

Results

Subjects had a mean baseline pre- and post-bronchodilator FEV1 of 71% and 88% predicted, respectively. Significant improvements in change from baseline trough FEV1 were observed for UMEC 15.6 OD (0.066 L; p = 0.036) and UMEC 125 OD (0.088 L; p = 0.005) versus placebo, but not other OD or BID doses. UMEC increased 0–24-h WM FEV1 versus placebo (0.068–0.121 L [p ≤ 0.017] with no clear dose–response). Treatment differences were similar for corresponding OD and BID doses in serial assessments. UMEC was rapidly absorbed, with evidence of some accumulation. The incidence of on-treatment adverse events was 9–21% for UMEC and 12% for placebo. There were no treatment-related effects on laboratory parameters.

Conclusion

The modest trough FEV1 improvements did not conclusively support a therapeutic benefit of UMEC in non-ICS treated patients with asthma.

ClinicalTrials.gov

NCT01641692.

Keywords

Asthma
Fixed-dose combination
Muscarinic antagonist
Inhaled corticosteroid
Trough FEV1

Abbreviations

Ae
amount of dose excreted unchanged in urine
AE
adverse event
ALT
alanine aminotransferase
AUC
area under the curve
BID
twice daily
bpm
beats per minute
CI
confidence interval
Cmax
maximum plasma concentration
COPD
chronic obstructive pulmonary disease
ECG
electrocardiogram
Fe
percentage of total dose excreted in urine
FEV1
forced expiratory volume in one second
GCP
Good Clinical Practice
HLQ
higher limit of quantification
ICS
inhaled corticosteroid
ICH
International Conference on Harmonisation
INR
international normalized ratio
LAMA
long-acting muscarinic antagonist
LLQ
lower limit of quantification
LS
least squares
NA
not available
NC
non-calculable
ND
not determined
NQ
non-quantifiable
OD
once daily
PEF
peak expiratory flow
PK
pharmacokinetic
PVC
premature ventricular contraction
SAE
serious adverse event
SD
standard deviation
SE
standard error
Tlast
time of the last point with quantifiable concentration
Tmax
time to maximum plasma concentration
ULN
upper limit of normal
UMEC
umeclidinium bromide
VPD
ventricular premature depolarization
WM
weighted mean

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